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Cerebrovascular Reactivity in American Football Players

Primary Purpose

Traumatic Brain Injury, Mild Traumatic Brain Injury, Post-Concussion Syndrome

Status
Terminated
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Sildenafil Citrate
Sponsored by
University of Pennsylvania
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Traumatic Brain Injury focused on measuring TBI, CVR, Hypercapnia, fNIRS, functional magnetic resonance imaging (fMRI), American football

Eligibility Criteria

40 Years - 65 Years (Adult, Older Adult)MaleDoes not accept healthy volunteers

Inclusion Criteria:

  1. Age 40-65 years
  2. Former National Football League (NFL) players or former varsity college football players
  3. Ability to undergo MRI scanning
  4. Ability to read, write, and speak English
  5. Stable doses of concomitant medications for last 2 weeks prior to enrollment
  6. Diagnosis of post-concussive syndrome according to Diagnostic and Statistical Manual 5 (DSM-5) criteria

Exclusion Criteria:

  1. Contraindication to sildenafil
  2. Past medical history or evidence of penetrating brain injury
  3. Daily therapy with a PDE5 inhibitor within the past 2 months, or taken as needed within past 4 weeks
  4. History or evidence of pre-existing disabling neurological or psychiatric disorder not related to previous head injuries
  5. History of melanoma
  6. History of diagnosed obstructive/ restrictive pulmonary disease 7 .) Contraindication to MRI

Sites / Locations

  • Penn Presbyterian Medical Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Sildenafil Citrate

Arm Description

Open label treatment with forced titration of sildenafil citrate.

Outcomes

Primary Outcome Measures

Effect of single dose sildenafil citrate treatment on global blood oxygen level-dependent (BOLD) response to hypercapnia.
Determine if single dose treatment with sildenafil (60 mg orally) is effective in increasing the global BOLD response to hypercapnia (5% CO2).

Secondary Outcome Measures

Effect of single dose sildenafil citrate treatment on functional near-infrared spectroscopy (fNIRS) response to hypercapnia.
Determine if single dose treatment with sildenafil (60 mg orally) is effective in increasing the functional near-infrared spectroscopy (fNIRS) response to hypercapnia (5% CO2).
Maximum tolerable dose of sildenafil therapy without severe adverse events.
The number of participants reporting treatment-related adverse events (AEs) and serious adverse events (SAEs) will be monitored after each dose increase. AEs and SAEs are assessed using CTCAE, v4.0.

Full Information

First Posted
October 11, 2017
Last Updated
September 16, 2022
Sponsor
University of Pennsylvania
Collaborators
Boston University
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1. Study Identification

Unique Protocol Identification Number
NCT03417492
Brief Title
Cerebrovascular Reactivity in American Football Players
Official Title
Cerebrovascular Reactivity Assessed With Functional Near-infrared Spectroscopy and Magnetic Resonance Imaging as a Biomarker of Traumatic Microvascular Injury in American Football Players
Study Type
Interventional

2. Study Status

Record Verification Date
September 2022
Overall Recruitment Status
Terminated
Why Stopped
Difficulty enrolling participants due to COVID emergency, and planned start of new study to address this question in a more rigorous fashion.
Study Start Date
March 1, 2018 (Actual)
Primary Completion Date
June 30, 2022 (Actual)
Study Completion Date
June 30, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Pennsylvania
Collaborators
Boston University

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
Investigators will measure cerebrovascular reactivity (CVR) using functional near-infrared spectroscopy (fNIRS) and magnetic resonance imaging (MRI) during the chronic phase after repetitive mild traumatic brain injury (rmTBI) as a biomarker of traumatic cerebrovascular injury (TCVI). We hypothesize that CVR will be decreased in patients with rmTBI and that these decreases will correlate with clinical outcomes. Furthermore, we predict that 5 week administration of a phosphodiesterase 5 (PDE5) inhibitor, sildenafil citrate, will augment CVR in patients with a history rmTBI.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Traumatic Brain Injury, Mild Traumatic Brain Injury, Post-Concussion Syndrome
Keywords
TBI, CVR, Hypercapnia, fNIRS, functional magnetic resonance imaging (fMRI), American football

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Model Description
Open-label, non-placebo controlled
Masking
None (Open Label)
Allocation
N/A
Enrollment
7 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Sildenafil Citrate
Arm Type
Experimental
Arm Description
Open label treatment with forced titration of sildenafil citrate.
Intervention Type
Drug
Intervention Name(s)
Sildenafil Citrate
Other Intervention Name(s)
Open label forced titration with sildenafil citrate.
Intervention Description
Three 20 mg capsules for the single dose studies. For the 5-week treatment phase, subjects will be assigned to a titration of doses for the 5 week duration of the study. Subjects will be instructed to take 20mg twice per day for 3 days, then 40mg twice per day for 3 days, and then 80mg twice per day for 4 weeks.
Primary Outcome Measure Information:
Title
Effect of single dose sildenafil citrate treatment on global blood oxygen level-dependent (BOLD) response to hypercapnia.
Description
Determine if single dose treatment with sildenafil (60 mg orally) is effective in increasing the global BOLD response to hypercapnia (5% CO2).
Time Frame
Immediate
Secondary Outcome Measure Information:
Title
Effect of single dose sildenafil citrate treatment on functional near-infrared spectroscopy (fNIRS) response to hypercapnia.
Description
Determine if single dose treatment with sildenafil (60 mg orally) is effective in increasing the functional near-infrared spectroscopy (fNIRS) response to hypercapnia (5% CO2).
Time Frame
Immediate
Title
Maximum tolerable dose of sildenafil therapy without severe adverse events.
Description
The number of participants reporting treatment-related adverse events (AEs) and serious adverse events (SAEs) will be monitored after each dose increase. AEs and SAEs are assessed using CTCAE, v4.0.
Time Frame
5 weeks
Other Pre-specified Outcome Measures:
Title
Effect of 5 weeks sildenafil treatment on CVR as measured by BOLD response to hypercapnia.
Description
To evaluate the effects of 5 weeks of treatment on CVR by measuring BOLD signal in response to hypercapnia after 5 week treatment with sildenafil, compared to within-subject CVR response before sildenafil treatment.
Time Frame
5 weeks
Title
Effect of 5 weeks sildenafil treatment on CVR as measured by fNIRS response to hypercapnia.
Description
To evaluate the effects of 5 weeks of treatment on CVR by measuring fNIRS signal in response to hypercapnia after 5 week treatment with sildenafil, compared to within-subject CVR response before sildenafil treatment.
Time Frame
5 weeks
Title
Effect of 5 weeks of sildenafil treatment on attention using Trail Making Test Part A.
Description
To evaluate the effects of 5 weeks of treatment with sildenafil citrate on attention, measured using the Trail Making Test Part A.
Time Frame
5 weeks
Title
Effect of 5 weeks of sildenafil treatment on attention using the Digit Symbol Modalities Test.
Description
To evaluate the effects of 5 weeks of treatment with sildenafil citrate on attention, measured using the Digit Symbol Modalities Test.
Time Frame
5 weeks
Title
Effect of 5 weeks of sildenafil treatment on executive function using the Trail Making Test Part B.
Description
To evaluate the effects of 5 weeks of treatment with sildenafil citrate on executive function, measured using the Trail Making Test Part B.
Time Frame
5 weeks
Title
Effect of 5 weeks of sildenafil treatment on executive function using the Neuropsychological Assessment Battery (NAB) mazes.
Description
To evaluate the effects of 5 weeks of treatment with sildenafil citrate on executive function, measured using the Neuropsychological Assessment Battery (NAB) mazes.
Time Frame
5 weeks
Title
Effect of 5 weeks of sildenafil treatment on executive function using the Controlled Oral Word Association Test (COWAT).
Description
To evaluate the effects of 5 weeks of treatment with sildenafil citrate on executive function, measured using the Controlled Oral Word Association Test (COWAT).
Time Frame
5 weeks
Title
Effect of 5 weeks of sildenafil treatment on language and memory using the Animal Fluency test.
Description
To evaluate the effects of 5 weeks of treatment with sildenafil citrate on language and memory, measured using the Animal Fluency test.
Time Frame
5 weeks
Title
Effect of 5 weeks of sildenafil treatment on language and memory using the NAB List Learning test.
Description
To evaluate the effects of 5 weeks of treatment with sildenafil citrate on language and memory, measured using the NAB List Learning test.
Time Frame
5 weeks
Title
Effect of 5 weeks of sildenafil treatment on daily function using the Functional Activities Questionnaire.
Description
To evaluate the effects of 5 weeks of treatment with sildenafil citrate on daily function, measured using the Functional Activities Questionnaire. The questionnaire requires the subject to rate the level of difficulty/dependency of each task listed (rating range from 0-3). A lower score indicates less difficulty in the listed activities while a higher score indicates more difficulty. The ratings are summed and the total score is reported (range 0-30).
Time Frame
5 weeks

10. Eligibility

Sex
Male
Minimum Age & Unit of Time
40 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Age 40-65 years Former National Football League (NFL) players or former varsity college football players Ability to undergo MRI scanning Ability to read, write, and speak English Stable doses of concomitant medications for last 2 weeks prior to enrollment Diagnosis of post-concussive syndrome according to Diagnostic and Statistical Manual 5 (DSM-5) criteria Exclusion Criteria: Contraindication to sildenafil Past medical history or evidence of penetrating brain injury Daily therapy with a PDE5 inhibitor within the past 2 months, or taken as needed within past 4 weeks History or evidence of pre-existing disabling neurological or psychiatric disorder not related to previous head injuries History of melanoma History of diagnosed obstructive/ restrictive pulmonary disease 7 .) Contraindication to MRI
Facility Information:
Facility Name
Penn Presbyterian Medical Center
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States

12. IPD Sharing Statement

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Cerebrovascular Reactivity in American Football Players

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